Engineered M2 macrophage-derived extracellular vesicles with platelet membrane fusion for targeted therapy of atherosclerosis

Atherosclerosis is featured as chronic low-grade inflammation in the arteries, which leads to the formation of plaques rich in lipids. M2 macrophage-derived extracellular vesicles (M₂EV) have significant potential for anti-atherosclerotic therapy. However, their therapeutic effectiveness has been hindered by their limited targeting capability in vivo. The objective of this study was to create the P-M₂EV (platelet membrane-modified M₂EV) using the membrane fusion technique in order to imitate the interaction between platelets and macrophages. P-M₂EV exhibited excellent physicochemical properties, and microRNA (miRNA)-sequencing revealed that the extrusion process had no detrimental effects on miRNAs carried by the nanocarriers. Remarkably, miR-99a-5p was identified as the miRNA with the highest expression level, which targeted the mRNA of Homeobox A1 (HOXA1) and effectively suppressed the formation of foam cells in vitro. In an atherosclerotic low-density lipoprotein receptor-deficient (Ldlr^-/-) mouse model, the intravenous injection of P-M₂EV showed enhanced targeting and greater infiltration into atherosclerotic plaques compared to regular extracellular vesicles. Crucially, P-M₂EV successfully suppressed the progression of atherosclerosis without causing systemic toxicity. The findings demonstrated a biomimetic platelet-mimic system that holds great promise for the treatment of atherosclerosis in clinical settings.